A systematic review evaluating the efficacy and factor consumption of long-acting recombinant factor VIII products for the prophylactic treatment of hemophilia A

Figures & data

Table 1. Literature search terms.

PubMed
1	“Factor VIII deficiencies” OR “Factor VIII deficiency” OR “FVIII deficiencies” OR “FVIII deficiency”
2	“Hemophilia A” OR “Haemophilia A”
3	“Factor VIII/administration and dosage”[Mesh] OR “FVIII/administration and dosage”[Mesh] OR “Factor 8/administration and dosage”[Mesh]
4	((“Factor VIII” OR “FVIII” OR “Factor 8”) AND (“treatment” OR “drug” OR “therapy” OR “concentrate” OR “recombinant”)) OR “rFVIII”
5	“rFVIII-SC” OR “AFSTYLA” OR “rFVIII-SingleChain” OR “CSL627” OR “lonoctocog al*” OR “Advate” OR “octocog al*” OR “rurioctocog al*” OR “rAHF-PFM” OR “Novo8” OR “NovoEight” OR “turoctocog al*” OR “N8” OR “BAY 81-8973” OR “BAY 14-2222” OR “Helixate” OR “Iblias” OR “Kogenate” OR “Kovaltry” OR “rFVIII-FS” OR “Nuwiq” OR “simoctocog al*” OR “rhFVIII” OR “Eloctate” OR “Elocta” OR “efmoroctocog al*” OR “efraloctocog al*” OR “FVIII-Fc” OR “Adynovate” OR “Adynovi” OR “BAX-855” OR “PEG rFVIII” OR “rurioctocog alfa pegol” OR “rurioctocog alpha pegol” OR “BAY 94-9027” OR “damoctocog alfa pegol” OR “damoctocog alpha pegol” OR “rFVIII glycopegylated” OR “PEGylated BDD-rFVIII” OR “N8-GP” OR “turoctocog alfa pegol” OR “turoctocog alpha pegol” OR “rFVIII glycopegylated”
6	“bleed” OR “bleeding” OR “bleedings” OR “bleeds” OR “Blood loss” OR “hemorrhag*” OR “haemorrhag*” OR “ABR” OR “AsBR” OR “jABR” OR “AjBR” OR “annualized bleeding rate” OR “annualized spontaneous bleeding rate” OR “joint annualized bleeding rate” OR “annualised bleeding rate” OR “annualised spontaneous bleeding rate” OR “joint annualised bleeding rate” OR “consumption” OR “trough”
FINAL	(1 OR 2) AND (3 OR 4 OR 5) AND (6)
EMBASE
1	“Factor VIII deficiencies” OR “Factor VIII deficiency” OR “FVIII deficiencies” OR “FVIII deficiency”
2	“Hemophilia A” OR “Haemophilia A”
3	((“Factor VIII” OR “FVIII” OR “Factor 8”) AND (“treatment” OR “drug” OR “therapy” OR “concentrate” OR “recombinant”)) OR “rFVIII”
4	“rFVIII-SC” OR “AFSTYLA” OR “rFVIII-SingleChain” OR “CSL627” OR “lonoctocog al*” OR “Advate” OR “octocog al*” OR “rurioctocog al*” OR “rAHF-PFM” OR “Novo8” OR “NovoEight” OR “turoctocog al*” OR “N8” OR “BAY 81-8973” OR “BAY 14-2222” OR “Helixate” OR “Iblias” OR “Kogenate” OR “Kovaltry” OR “rFVIII-FS” OR “Nuwiq” OR “simoctocog al*” OR “rhFVIII” OR “Eloctate” OR “Elocta” OR “efmoroctocog al*” OR “efraloctocog al*” OR “FVIII-Fc” OR “Adynovate” OR “Adynovi” OR “BAX-855” OR “PEG rFVIII” OR “rurioctocog alfa pegol” OR “rurioctocog alpha pegol” OR “BAY 94-9027” OR “damoctocog alfa pegol” OR “damoctocog alpha pegol” OR “rFVIII glycopegylated” OR “PEGylated BDD-rFVIII” OR “N8-GP” OR “turoctocog alfa pegol” OR “turoctocog alpha pegol” OR “rFVIII glycopegylated”
5	“bleed” OR “bleeding” OR “bleedings” OR “bleeds” OR “Blood loss” OR “hemorrhag*” OR “haemorrhag*” OR “ABR” OR “AsBR” OR “jABR” OR “AjBR” OR “annualized bleeding rate” OR “annualized spontaneous bleeding rate” OR “joint annualized bleeding rate” OR “annualised bleeding rate” OR “annualised spontaneous bleeding rate” OR “joint annualised bleeding rate” OR “consumption” OR “trough”
FINAL	(1 OR 2) AND (3 OR 4) AND (5)

Table 2. Inclusion and exclusion criteria.

	Inclusion criteria	Exclusion criteria
Study type	Phase III trials Full original articles	Review papers Conference abstracts or proceedings Opinion pieces Guidelines Meta-analyses Systematic reviews Editorials Commentaries Case reports Case series Extension studies Secondary articles Retracted articles
Subjects	Adult human subjects (aged 12–65 years) Diagnosed with moderate-to-severe hemophilia A (FVIII levels ≤ 2%) Previously treated Receiving LA rFVIII prophylactically	Animal models In vitro studies Ex vivo studies Healthy volunteers Surgical patients Patients receiving pdFVIII Patients receiving standard-acting rFVIII

Abbreviations. LA, long-acting; pdFVIII, plasma-derived FVIII; rFVIII, recombinant FVIII.

Figure 1. PRISMA diagram detailing the screening process.

Table 3. Study characteristics of included articles.

Study	Product	Design	Phase	Subjects (n)	Endogenous FVIII levels	Median treatment duration (weeks)
Mahlangu et al.^8	rVIII-SingleChain	Open-label, non-randomized	I/III	173 ITT (175 enrolled), 146 prophylaxis	<1%	Not reported
Mahlangu et al.^9	rFVIIIFc	Open-label, partially randomized	III	165 ITT (165 enrolled), 142 prophylaxis	<1%	(min, max) 32.1 (9, 54)
Konkle et al.^12	BAX 855	Open-label, non-randomized	II/III	138 ITT (138 enrolled), 120 prophylaxis	<1%	Not reported
Giangrande et al.^11	N8-GP	Open-label, non-randomized	III	186 ITT (186 enrolled), 175 prophylaxis	<1%	(min, max) Days: 299 (5, 593)
Reding et al.^10	BAY 94-9027	Partially randomized, open-label	II/III	132 ITT (134 enrolled), 114 prophylaxis	<1%	Mean (SD) Days: 246.7 (41.3)

Abbreviation. ITT, intent-to treat.

Table 4. Details of bleeding rates and consumption in LA rFVIII studies identified by the systematic review.

Product, dose and regimen	Patients (n); Age (years), mean (SD)	ABR, median (IQR), mean [SD]	AsBR, median (IQR), mean [SD]	AjBR, median (IQR), mean [SD]	Consumption (IU/kg/year), median	Consumption (IU/kg/year), mean
rVIII-SingleChain; 20–50 IU/kg 2 or 3 × weekly^8	n = 126; 29.7 (11.1)	1.14 (0.00–4.30), 3.32 [5.34]	0.00 (0.00–2.66), 2.33 [5.07]	Not reported	4282.9	4472.5 (SD: 1794.0)
rFVIIIFc; 25 IU/kg on day 1, 50 IU/kg on day 4, followed by 25–65 IU/kg, every 3–5 days^9	n = 117; 29 (12, 65)^§	1.6 (0.0–4.7), Not reported	0.0 (0.0–2.0), Not reported	0.0 (0.0–1.7),^†† Not reported	4050.8^‡‡	4440.8^‡‡
BAX 855; 45 ± 5 IU/kg 2 × weekly^12	n = 120; 28 (12, 58)^§	1.9 (0.0–5.8), 3.7 [4.7]	0 (0.0–2.2), 2.1 [3.5]	0.0 (0.0–2.0), 1.8 [3.0]	4546^§§	Not reported
N8-GP; 50 IU/kg every 4 days^11	n = 175; 30.6 (12.5)	1.18 (0.00–4.25), 3.04 [2.45–3.77]**	0.00 (0.00–1.82), Not reported	0.85 (0.00–2.84), Not reported	Not reported	4845
BAY 94-9027; 30–40 IU/kg 2 × weekly^†Citation10	n = 13; 31.4 (11.6)	4.1 (2.0–10.6), Not reported	Not reported	Not reported	Not reported	4497.8
BAY 94-9027; 30–40 IU/kg 2 × weekly^‡^10	n= 11; 33.1 (11.0)	1.9 (0.0–5.2), Not reported	Not reported	Not reported	Not reported	3341.1

Abbreviations. IQR, interquartile range; IU, international units; SD, standard deviation.

Where data were available for more than one prophylaxis regimen, information is presented for the regimen closest to the initial regimen as recommended in the US product label.

^†Group who experienced >1 bleed during the study run-in phase so were not eligible for randomization; ^‡group who experienced <1 bleed in the study run-in phase who were eligible for randomization but not randomized as the randomization arms were full; ^§Median (min, max); **Poisson estimate [95% CI]; ^††Spontaneous joint bleeds; ^‡‡Calculated from weekly dose (median 77.9, mean 85.4); ^§§Calculated from median dose per infusion (44.6) and median number of infusions per week (1.96).

Mahlangu J, Kuliczkowski K, Karim FA, et al. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood. 2016;128(5):630–637.

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Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123(3):317–325.

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Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126(9):1078–1085.

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Giangrande P, Andreeva T, Chowdary P, et al. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost. 2017;117(2):252–261.

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Reding MT, Ng HJ, Poulsen LH, et al. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost. 2017;15(3):411–419.

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